评估胰岛素分泌及胰岛素敏感性选择降糖药物的临床多中心研究

目的评价糖尿病病理生理变化对新诊断的2型糖尿病患者治疗的指导意义。方法按照精氨酸刺激试验的结果，将322例新诊断2型糖尿病患者分为一相胰岛素分泌正常组和低下组，将前者随机分配至瑞格列奈、罗格列酮及二甲双胍治疗组，后者随机分配至瑞格列奈、罗格列酮及格列吡嗪治疗组。结果（1）各药物治疗组，用药后3个月、6个月的空腹血糖、餐后2h血糖及HbA1C均较基线明显降低（均P〈0．01）。治疗后6个月HbA1C控制理想的总体达标率为63．5％。（2）在一相胰岛素分泌正常组，罗格列酮治疗后血糖校正后的精氨酸试验胰岛素曲线下面积（AUC）明显增加，胰岛素原显著减少（P〈0．01），二甲双胍治疗后胰岛素抵抗指数（HOMA—IR）较基线显著降低（P〈0．05）。（3）在一相胰岛素分泌低下组，瑞格列奈或格列吡嗪治疗后的精氨酸试验的2、4、6min真胰岛素均值与空腹真胰岛素的差值（△TI）、血糖校正后精氨酸试验的结果（ATI／PG）、AUC及真胰岛素（TI）明显增高（P〈0．05或P〈0．01），罗格列酮组治疗后的ATI／PG与AUC显著增加，而HOMA—IR及胰岛素原较治疗前明显减少（均P〈0．01）。结论（1）基于糖尿病病理生理变化正确评估的药物治疗，可有效控制新诊断2型糖尿病患者的糖代谢紊乱。（2）瑞格列奈及格列吡嗪可增加2型糖尿病患者的一相胰岛素分泌及真胰岛素水平。（3）罗格列酮不仅可以增加机体的胰岛素敏感性，减少胰岛素原的分泌，尚可改善一相胰岛素分泌低下者的一相胰岛素分泌功能。（4）新诊断2型糖尿病患者血糖的有效控制，主要与机体胰岛素分泌功能的改善及胰岛素敏感性的增加有关。     

新诊断2型糖尿病病人脂代谢紊乱状态与胰岛素抵抗及胰岛素分泌缺陷

目的 观察新诊断的2型糖尿病病人脂代谢紊乱状态与胰岛素抵抗及胰岛素分泌缺陷的关系。方法 143例新诊断的2型糖尿病病人，根据美国ATP Ⅲ标准分为血脂正常组，高甘油三酯组、高胆固醇组、混合性高脂组，应用稳态模型评估法评价胰岛素敏感性及胰岛B细胞功能，探讨各种类型的脂代谢紊乱与胰岛素抵抗及胰岛素分泌缺陷的关系。结果 新诊断的2型糖尿病病人血脂紊乱发生率为56．6％，高甘油三酯组的HOMA-IR较正常组显著升高。各组HOMAp无显著差别。结论 新诊断的2型糖尿病病人脂代谢紊乱类型以高TC／LDL最常见，但高TG者的胰岛素抵抗程度更为严重。     

不同糖耐量个体胰岛素抵抗与胰岛β细胞功能观察及评价

目的评价正常糖耐量（NGT）、糖调节受损（IGR）、2型糖尿病（T2DM）个体胰岛素抵抗及胰岛β细胞功能，为临床早期综合干预提供科学依据。方法244例入选者，行口服葡萄糖耐量试验，根据1999年WHO糖尿病诊断标准分为NGT组（86例）、IGR组（58例）及T2DM组（100例）。测量身高、体重、腰围、臀围及胰岛素释放，评价基础与糖负荷后胰岛素分泌功能及胰岛素抵抗。结果与NGT组比较，IGR组、T2DM组空腹血糖（FBG）、餐后2h血糖（P2BG）、糖化血红蛋白（HbA1C）均有统计学意义（P〈0．001）；胰岛素抵抗指数（HOMA-IR）在NGT组、IGR组和T2DM组依次增高（P〈0．001）；FBG、餐后2h血糖（P2BG）和胰岛素分泌指数（HOMA-IS）IGR组最高，胰岛素敏感指数（ISI）均值在IGR组最低，与NGT组、T2DM组比较差异有统计学意义（P〈0．01）。结论IGR人群存在基础和糖负荷后胰岛β细胞分泌功能异常及显著的胰岛素抵抗，是正常人发展至糖尿病者的移行阶段，应给予恰当的早期综合干预措施．预防糖尿病的发生。     

甲状腺功能亢进与胰岛素分泌功能和胰岛素抵抗的关系

目的探讨甲状腺功能亢进（甲亢）患者胰岛素分泌功能和胰岛素抵抗的变化。方法50例甲亢患者（甲亢组）行葡萄糖耐量试验,并以25例正常人作为对照组,分别测定两组空腹及餐后1、2h的血糖及胰岛素水平,计算胰岛素敏感指数、胰岛素抵抗指数及胰岛B细胞分泌功能指数并进行比较。结果甲亢组糖耐量正常15例,糖耐量减低25例,糖尿病10例。甲亢组胰岛素抵抗指数高于对照组,胰岛素敏感指数和胰岛B细胞分泌功能指数低于对照组,上述指标两组间比较差异均有统计学意义（P均〈0．05）。结论甲亢时可导致糖代谢紊乱,出现高血糖及高胰岛素血症,发生胰岛B细胞分泌功能下降及胰岛素抵抗。     

中国人糖耐量异常与胰岛素抵抗和胰岛素分泌

研究胰岛素抵抗和胰岛分泌缺陷与中国人糖耐量变化的关系。方法对４６６例（正常体重１８９例,超重／肥胖２７７例）正常糖耐量（ＮＧＴ）、糖耐量减退／空腹血糖减损（ＩＧＴ／ＩＦＧ）、２型糖尿病（ＤＭ）患者,用稳态模式评估法评价胰岛素抵抗及胰岛β细胞基础功能（ＨＯＭＡ－βｃｅｌｌ）并用糖负荷３０分钟净增胰鸟争增葡萄糖（△ｉ３０／△Ｇ３０）比值评价早期胰 岛素分泌反应。结果校正年龄,性别、体重指数（ＢＭＩ）、     

2型糖尿病病人高血压与胰岛素抵抗的关系

目的：探讨高血压与胰岛素抵抗之间的关系。方法：2型糖尿病高血压组123例,正常血压组120例,测定FPG,FINS,RC,TG,UA,MAU,血压,计算BMI,评价胰岛素抵抗和β细胞功能采用稳态模式评估法及改良胰岛素敏感性指数公式计算,结果：高血压组ISI显著低于正常血压组,HOMA－β cell,HOMA－IR显著高于正常血压组（P＜0．005）,正常体重者也有相同的结果（P＜0．05）,两组ISI与FPG,FINS,BIM均呈显著负相关（P＜0．05）,高血压组ISI与TC,TG,UA呈弱负相关（P＜0．5）,结论：2型糖尿病伴高血压病人无论是否肥胖都存在胰岛素抵抗,肥胖病人胰岛素抵抗理炙严重。     

老年人真胰岛素、胰岛素原水平及β细胞功能的变化

目的：探讨增龄对血清真胰岛素（TI）、胰岛素原（PI）水平及胰岛β细胞功能的影响。方法：筛选糖耐量正常的健康老年人7例（60－78岁）和中青年对照组60例（30－49岁）。测量血压，身高，体重，腰臂围，计算体重指数（BMI）和腰臂比（WHR）。测定空腹血脂及口服葡萄糖耐量试验各点的血糖、TI及PI浓度。结果：两组性别、BMI和空腹血糖相匹配（P＞0．05），老年组的WHR及血压高于对照组（P＜0．05）。老年组的空腹PI水平和PI／TI比值的几何均值分别为5．0pmol/L和0．21，明显高于对照组（分别为3．1pmol/L和0．13，均为P＜0．01），糖负荷后2h的PI和PI／TI值老年组也高于对照组（34．1pmol/L与20．5pmol/L，0．30与0．22，均为P＜0．05），但在调整WHR和血糖后统计学差别消失（P＞0．05）。两组间空腹和服糖后2h的TI水平，差异均无统计学意义（P＞0．05）。结论：老年人存在空腹高PI血症及PI不成比例的分泌增加，提示其β细胞功能异常，这一变化趋势可能与老年人易发2型糖尿病有关。     

早发2型糖尿病患者胰岛素抵抗及胰岛β细胞功能的变化

目的 比较早发和迟发2型糖尿病患者胰岛素抵抗及胰岛β细胞功能的变化.方法 94例2型糖尿病患者按诊断时年龄分为早发组和迟发组,比较两组在BMI、血糖、糖化血红蛋白（HbA1c）、血压、血脂、胰岛素抵抗指数（Homa-IR）、Homa-β细胞功能指数（HBCI）等方面的差异.结果 ①早发2型糖尿病组BMI、甘油三酯（TG）高于迟发组;高密度脂蛋白胆固醇（HDL）低于迟发组,差异有统计学意义（P＜0.05）,早发2型糖尿病家族聚集倾向更明显.②早发2型糖尿病组Homa-IR较迟发组增高（P＜0.05）,HBCI两组相似.结论 ①早发2型糖尿病组存在更显著的家族聚集性和更严重的代谢紊乱,②早发2型糖尿病组有更严重的胰岛素抵抗和相对的胰岛β细胞功能缺陷.     

2型糖尿病家系成员中的胰岛素抵抗与胰岛β—细胞功能状态的研究

目的研究胰岛素抵抗及胰岛紊分泌功能在2型糖尿病(DM)发生、发展中的作用.方法在2型DM家系成员中,对已诊断DM者按病程中位数分组,病程≤4年组153例,＜4年组129例.经口服葡萄糖耐量试验(OGTT),按1999年WHO糖尿病诊断标准,新诊断DM组72例.非DM者按HbAlc分组,HbAlc≤5.5%组78例,HbAlc＜5.5%组110例,计算各组HOMA模型胰岛素抵抗指数(HOMAIR)、β细胞功能指数(HOMAβ)及胰岛素敏感性指数(ISI),与无DM家族史的正常人98例比较.结果除HbAlc≤5.5%组外,家系各组HOMAIR均值高于正常对照,差异有显著性(P＜0.01).家系非DM两组HOMAβ高于正常对照(P＜0.01),DM各组HOMAβ低于正常对照(P＜0.01).结论北京地区2型DM家系中非DM一级亲属的胰岛素抵抗及糖耐量异常可能继发于胰岛素分泌功能异常增高,胰岛素分泌功能降低和胰岛素抵抗是发生糖尿病的主要机制.     

2型糖尿病患者一级亲属胰岛素抵抗与胰岛B细胞功能缺陷的临床研究

目的探讨胰岛素抵抗与胰岛B细胞功能缺陷在2型糖尿病(T2DM)发生中的作用。方法收集2004年4月至2005年6月解放军总医院门诊及住院T2DM患者的既往无糖耐量异常史的一级亲属,其中糖耐量正常(NGT)组174例、空腹血糖受损(IFG)或糖耐量低减(IGT)组55例,以及12例新发T2DM与同期收集的59例新发T2DM合并为新发糖尿病(T2DM)组;以其无糖尿病家族史的配偶或无血缘关系亲友中糖耐量正常者114名作为正常对照(NC)组。酶联免疫法测定血清真胰岛素(trueinsulin,TI)、胰岛素原(proinsulin,PI)。用胰岛素抵抗指数(Homa-IR)评价胰岛素抵抗。用空腹胰岛素原与空腹胰岛素比值(PI/TI)及B细胞功能指数(Homa-B),评估胰岛B细胞功能状态,并做对比分析。结果一级亲属中NGT组与NC组相比,Homa-IR显著高于NC组,PI/TI及Homa-B显著低于NC组。而且从NC至NGT至IGT或IFG至DM组,胰岛素抵抗进行性加重。胰岛B细胞分泌缺陷进行性加重,PI/TI逐渐升高,但LnHoma-B下降直至T2DM组才具显著意义(NC组为4.40±0.60,T2DM组为3.38±0.96)。结论T2DM患者一级亲属作为糖尿病的高危人群,在发生糖代谢异常前就存在胰岛素抵抗和胰岛分泌功能缺陷,且胰岛素抵抗和胰岛分泌功能缺陷与T2DM的发病相关;胰岛素原比例增加以及胰岛素原与真胰岛素比值升高是反映胰岛分泌功能缺陷的早期标志。     

Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues

The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence but not completely suppressed the occurrence of insulin allergy manifestations. Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), and the use of insulin analogues, resulting from the alteration in the amino acid sequence of the native insulin molecule, may influence the immunogenicity and antigenicity of native insulin. Instead of increasing allergy reactions, CSII has been reported to represent a successful alternative treatment in diabetic patients presenting local or generalized allergy to insulin or other components (zinc, protamine) of conventional treatment. Most recent reports concern CSII-treated patients using short-acting insulin analogues (essentially insulin lispro), although the precise role of these insulin analogues remains unclear as allergy to them has also been described. Finally, data on antigenicity and immunogenicity of long-acting insulin analogues (glargine, detemir), which may mimic the basal insulin delivery with CSII, remain scarce at present.     

Treatment of insulin lipoatrophy with monocomponent insulin

Summary A female diabetic with severe insulininduced lipoatrophy was successfully treated with a monocomponent (MC) Lente preparation. This patient was studied for over 6 years and, during periods of treatment with various insulins of different purity, a variety of reactions was observed in the adipose tissue. Evidence is presented that lipoatrophy may be caused by insulin impurities. Lipoatrophy occurring after treatment with recrystallized, mixed species Lente insulin was substantially reduced after treatment with 10 times recrystallized porcine Lente, but recurred on 4 times recrystallized beef Lente, also in areas where beef Lente was not injected. Beef insulin impurities seem more prone to produce lipoatrophy than pork insulin impurities. It is suggested that MC-insulin is the treatment of choice for this condition.     

Clinical utility of insulin and insulin analogs

Diabetes is a pandemic disease characterized by autoimmune, genetic and metabolic abnormalities. While insulin deficiency manifested as hyperglycemia is a common sequel of both Type-1 and Type-2 diabetes (T1DM and T2DM), it does not result from a single genetic defect—rather insulin deficiency results from the functional loss of pancreatic β cells due to multifactorial mechanisms. Since pancreatic β cells of patients with T1DM are destroyed by autoimmune reaction, these patients require daily insulin injections. Insulin resistance followed by β cell dysfunction and β cell loss is the characteristics of T2DM. Therefore, most patients with T2DM will require insulin treatment due to eventual loss of insulin secretion. Despite the evidence of early insulin treatment lowering macrovascular (coronary artery disease, peripheral arterial disease and stroke) and microvascular (diabetic nephropathy, neuropathy and retinopathy) complications of T2DM, controversy exists among physicians on how to initiate and intensify insulin therapy. The slow acting nature of regular human insulin makes its use ineffective in counteracting postprandial hyperglycemia. Instead, recombinant insulin analogs have been generated with a variable degree of specificity and action. Due to the metabolic variability among individuals, optimum blood glucose management is a formidable task to accomplish despite the presence of novel insulin analogs. In this article, we present a recent update on insulin analog structure and function with an overview of the evidence on the various insulin regimens clinically used to treat diabetes.     

Change of insulin dosage,circulating free and bound insulin and insulin antibodies on transferring diabetics from conventional to highly purified porcine insulin

Summary Fifty-eight patients on long term conventional mainly bovine insulins have been transferred to highly purified porcine insulin preparations. There was an overall reduction of 22% in daily insulin dosage and improved diabetic control as shown by decreased blood glucose concentration. Increased concentrations of serum free insulin and falls in serum bound insulin levels were also found. There were reductions in the serum binding capacities and affinity constants on changeover from conventional to highly purified insulin due to a combination of the effects of differential conventional/purified porcine binding and the substitution of a low antigenicity insulin. However, 12 of the patients receiving higher doses of insulin experienced marked hypoglycaemic reactions immediately on insulin change-over despite initial dosage reductions of 30% and prior to any changes in antibody characteristics.     

Reduction of postprandial glycemic excursions in patients with type 1 diabetes: a novel human insulin formulation versus a rapid-acting insulin analog and regular human insulin

Background:

Evaluation of postprandial glycemic excursions in patients with type 1 diabetes with three prandial insulins: VIAject™ (Linjeta™), an ultra-fast insulin (UFI); insulin lispro (LIS); and regular human insulin (RHI).

Methods:

After stabilization of preprandial glycemia, 18 patients received a subcutaneous injection with an individualized insulin dose prior to a meal.

Results:

Injection of UFI resulted in a more rapid insulin absorption than with either LIS or RHI (time to half-maximal insulin levels: 13.1 ± 5.2 vs 25.4 ± 7.6 and 38.4 ± 19.5 min; p = .001 vs LIS and p < .001 vs RHI, LIS vs. RHI p < .001). Maximal postprandial glycemia was lower with UFI (0–180 min; 157 ± 30 mg/dl; p = .002 vs RHI) and LIS (170 ± 42 mg/dl; p = .668 vs RHI) than after RHI (191 ± 46 mg/dl; RHI vs LIS p = .008). The difference between maximum and minimum glycemia was smaller with UFI (70 ± 17 mg/dl) than with either RHI (91 ± 33 mg/dl; p = .007 vs UFI) or LIS (89 ± 18 mg/dl; p = .011 vs UFI). Also, the area under the blood glucose profile was lower with UFI than with RHI (0–180 min; 21.8 ± 5.8 vs 28.4 ± 7.6 g·min/dl; p < .001).

Conclusions:

The rapid absorption of UFI results in a reduction of postprandial glycemic excursions.     

Effects of chronic systemic insulin delivery on insulin action in dogs

Summary The metabolic consequences of the prolonged systemic insulin delivery associated with human pancreas transplantation have not been precisely defined. To determine if systemic insulin delivery in the absence of immunosuppressive agents results in alterations in hepatic or extrahepatic insulin action, three groups of dogs were studied 2 months after either a sham operation or after their pancreatic venous drainage was severed and anastomosed to the inferior vena cava or portal vein (sham, peripheral and portal groups, respectively). The pattern of venous drainage was documented by measuring vena cava and portal insulin concentrations before and after glucose injection. Systemic insulin concentrations were higher (p<0.05) in the peripheral group than in the portal group both following a 14-h fast and after intravenous glucose. During a hyperinsulinaemic euglycaemic clamp (1 mU·kg^–1·min^–1), glucose utilization (measured using [6³H] glucose) was slightly lower (p=0.07) in the peripheral than in the portal group. Hepatic glucose release was equal in all groups. Carbon dioxide incorporation into glucose (an estimate of gluconeogenesis) was higher in the portal than peripheral group in the fasted state but not during insulin infusion. Plasma concentrations and flux rates of fatty acids and amino acids did not differ between groups. We conclude that chronic systemic insulin delivery results in a) systemic but not portal hyperinsulinaemia, b) a minimal impairment in insulin-stimulated glucose uptake, without altering insulin-induced suppression of hepatic glucose release, and c) no effect on fatty acid or amino acid turnover. Although chronic systemic insulin delivery appears to have a minimal effect on insulin action, it remains to be determined whether it has other deleterious effects such as enhancing atherogenesis.     

Continuous subcutaneous insulin infusion with short-acting insulin analogues or human regular insulin: efficacy, safety, quality of life, and cost-effectiveness

Portable insulin infusion devices are effective and safe insulin delivery systems for managing diabetes mellitus, especially type 1 diabetes. Rapidly absorbed insulin analogues, such as insulin lispro or insulin aspart, may offer an advantage over regular human insulin for insulin pumps. Several open-label randomised crossover trials demonstrated that continuous subcutaneous insulin infusion (CSII) with insulin lispro provided a better control of postprandial hyperglycaemia and a slightly but significantly lower glycated haemoglobin level, with lower daily insulin requirement and similar or even less hypoglycaemic episodes. A CSII study comparing insulin lispro and insulin aspart demonstrated similar results with the two analogues, and better results than those with regular insulin. Because these analogues have a quicker onset and a shorter duration of action than regular insulin, one might expect an earlier and greater metabolic deterioration in case of CSII interruption, but a more rapid correction of metabolic abnormalities after insulin boluses when reactivating the pump. These expectations were confirmed in randomised protocols comparing the metabolic changes occurring during and after CSII interruption of various durations when the pump infused either insulin lispro or regular insulin. The extra cost resulting from the use of CSII and insulin analogues in diabetes management should be compensated for by better metabolic control and quality of life. In conclusion, CSII delivering fast-acting insulin analogues may be considered as one of the best methods to replace insulin in a physiological manner by mimicking meal and basal insulin requirements, without higher risk of hypoglycaemia or ketoacidosis in well-educated diabetic patients.     

Short-acting insulin analogues vs. regular human insulin in type 2 diabetes: a meta-analysis

Aim:  Short-acting insulin analogues, in comparison with regular human insulin (HRI), provide a greater control of postprandial glucose, while their superiority on haemoglobin A1c (HbA1c) is controversial.
Method:  All randomized controlled trials (RCTs) with a duration >4 weeks comparing short-acting insulin analogues (lispro, aspart or glulisine) with HRI in type 2 diabetic patients were retrieved; data on HbA1c and postprandial glucose et end-point and incidence of severe hypoglycaemia were extracted and meta-analysed.
Results:  A total of 13 RCTs (7, 4 and 2 with lispro, aspart and glulisine, respectively) were retrieved and included in the analysis. Short-acting analogues reduced HbA1c by 0.4% (0.1–0.6%) (p = 0.027) in comparison with HRI. A significant improvement was observed also in self-monitored 2 h postbreakfast and dinner blood glucose. The overall rate of severe hypoglycaemia was not significantly different with short-acting analogues and HRI [Mantel–Haenszel odds ratio for 95% confidence interval 0.61 (0.25–1.45)].
Conclusion:  In type 2 diabetic patients, short-acting insulin analogues provide a better control of HbA1c and postprandial glucose than regular human insulin, without any significant reduction of the risk of severe hypoglycaemia.     

Binding of human,porcine and bovine insulin to insulin receptors from human brain,muscle and adipocytes and to expressed recombinant alternatively spliced insulin receptor isoforms

Summary Previous studies have suggested that human and porcine insulin exert identical effects on blood glucose and counter-regulatory hormones but elicit different neurophysiological reactions. A major goal of the present study was to investigate whether this could be caused by different relative affinities of the insulins from different species to insulin receptors from the brain compared to other tissues. Insulin receptors isolated from human brain, muscle or adipocytes as well as from cultured cells over-expressing either of the human insulin receptor isoforms (exon 11– or exon 11 + ) were immobilized to microwells coated with monoclonal anti-insulin receptor antibody. Subsequently the binding of human, porcine and bovine insulin was measured. While the receptors derived from the different tissues had different affinities for insulin, there were no tissue-specific differences in the relative binding of the insulins of the three species. The insulins of the three species were also not different with regard to their binding to the receptor isoforms. Finally, in human brain homogenates no differences in the degradation rates for human, porcine and bovine insulin were detected. Thus, our data do not support the hypothesis that different neurophysiological reactions during hypoglycaemia due to human or porcine insulin are caused by differences of the binding of the insulins to human brain insulin receptors or their degradation in the human brain. [Diabetologia (1995) 38: 757–763] Received: 18 July 1994 and in revised form: 6 December 1994     

B1-3,5-diiodotyrosine insulin: A valid tracer for insulin

Summary Insulin, specifically substituted at the Phe^B1 position with 3,5-diiodotyrosine, has been tested in several biological and immunological systems. Immunoreactivity was assessed using antisera specific for different parts of the insulin molecule. Biological activity in vitro was estimated on isolated rat fat cells. In vivo bioactivity (hypoglycaemia) and metabolism (metabolic and urinary clearance rates, half-life, apparent distribution space) were measured by infusion of the material into greyhounds. The results indicated that this B1-labelled insulin preparation was biologically fully active and, unlike randomly labelled preparations of iodoinsulin, was metabolised with kinetics indistinguishable from those of the unlabelled hormone. We suggest that this material is a valid tracer for insulin, fulfilling the criteria of high specific activity and biological identity to the native hormone.